The power of intravenous high-dose vitamin C in Cancer Therapy

Increasing research is starting to show the myriad of anticancer properties, such as targeting vulnerabilities many cancer cells share, such as high-dose vitamin C, redox imbalance, epigenetic reprogramming and oxygen-sensing regulation[1]

What is Vitamin C?

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin with essential and antioxidant properties. Its most notable health benefit is its ability to help reduce oxidative stress throughout the body due to its antioxidant activity.

Vitamin C is naturally present in some foods—mainly fruits and vegetables—and is also added to many food products. It is also available in supplement form either on its own or in combination with other nutrients and vitamins as well as in high dose iv drips.

Vitamin C plays an important role in the body, in addition to acting as an antioxidant. It helps form collagen, which forms the basis of bones, cartilage, skin and tendons; maintains healthy skin; repairs tissue damage caused by injury or disease; strengthens the immune system's ability to fight infection; supports healthy iron absorption; and improves wound healing times. Research suggests that higher doses of vitamin C may have additional benefits for certain health conditions.

What is the latest research about the benefits of vitamin c in cancer therapy?

A vast number of studies have shown encouraging the anti-cancer activity of vitamin C at high doses in various cancer types [3].

The most investigated have been leukaemia [20–24], colon cancer [13–20], melanoma [21–25], pancreatic cancer [2, 19, 26] and prostate cancer [27–29].

Similar results have been described for the treatment of non-small-cell lung cancer (NSCLC) [4], breast cancer [29, 30], ovarian cancer [29, 31, 32], hepatocellular carcinoma [33, 34], malignant mesothelioma [35, 36], thyroid cancer [37, 38], oral squamous cell carcinoma [39], neuroblastoma [40] and glioma, including the difficult-to-treat glioblastoma multiform (GBM) [4, 41, 42].

One notable example of the progress in vitamin C pre-clinical research is the recent work in hard-to-treat Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) driven tumours, such as KRAS mutant colorectal cancer (CRC) [13, 15, 20]. Based on prior studies by Yun et al. [25] and Aguilera et al. [25], Cenigaonan- dia-Campillo et al. [15] used elevated doses of Vitamin C (5–10mM) in KRAS mutant CRC tumours, both in vitro and in vivo.

They showed that Vitamin C could target common metabolic aberrancies by decreasing adenosine triphosphate (ATP) and glucose transporter 1 (GLUT-1) levels, as well as by dissipating the mitochondrial membrane potential, which could sensitize KRAS mutant CRC cells to current treatments such as chemotherapy.

Given the importance of developing better treatments for patients with KRAS driven tumours, non-toxic combinations with vitamin C are also being explored and will be discussed in the following section 2.

In the majority of cancer types, most of the in vivo studies have shown inhibition of tumour growth (40–60%) by using elevated doses of ascorbate (1-4g/ kg) either intravenously (IV) or intraperitoneally (IP) [13, 43–45]

According to research[47], a fully competent immune system is required to maximize the antiproliferative effect of vitamin C in breast, colorectal, melanoma, and pancreatic tumours. High-dose vitamin C modulates infiltration of the tumour microenvironment by cells of the immune system and delays cancer growth in a T cell-dependent manner.

Vitamin C not only enhances the cytotoxic activity of adoptively transferred CD8 T cells but also cooperates with immune checkpoint therapy (ICT) in several cancer types.

Combination of this vitamin and ICT can be curative in models of mismatch repair-deficient tumors with high mutational burden.

More literature [48] states that mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC).

Early-phase clinical trials have confirmed the safety and indicated the efficacy of IVC in eradicating tumour cells of various cancer types.

In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as a cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and boosting immune response.

Moreover, high-dose IVC is powerful as an adjuvant treatment for cancer, acting synergistically with many standards (chemo-) therapies, as well as a method for mitigating the toxic side effects of chemotherapy.

In more scientific terms, research[49] has shown that due to vitamin C complex pharmacokinetics, only intravenous administration allows reaching sufficiently high plasma concentrations required for most of the antitumor effects observed in preclinical studies (>0.250 mM).

Moreover, vitamin C entry into cells is tightly regulated by SVCT and GLUT transporters and is cell type-dependent. Significantly, besides its well-recognized pro-oxidant effects, vitamin C modulates TET enzymes promoting DNA demethylation and acts as a cofactor of HIF hydroxylases, whose activity is required for HIF-1α proteasomal degradation.

Furthermore, at pharmacological concentrations lower than those required for its pro-oxidant activity (<1 mM), vitamin C in specific genetic contexts may alter the DNA damage response by increasing 5-hydroxymethylcytosine levels.

These more recently described vitamin C mechanisms offer new treatment opportunities for tumours with specific molecular defects (e.g., HIF-1α over-expression or TET2, IDH1/2, and WT1 alterations).

Moreover, vitamin C action at DNA levels may provide the rationale basis for combination therapies with PARP inhibitors and hypomethylating agents.

Vitamin C monotherapy in palliative care and quality of life (EOL)

In palliative care, high-dose VitC is currently gaining ground due to its highly safe and tolerable profile. Not only is high-dose vitamin C known to relieve pain in cancer patients [6], extensive clinical evidence suggests that it has a significant positive impact on patients’ well-being [1, 2-5, 7-10].

This might be due to the frequent hypovitaminosis and vitamin C deficiency in cancer patients [6, 11, 12], which are commonly enhanced by anti-neo-plastic treatments [3].

For instance, a retrospective, multicentre, epidemiological cohort study [3] showed amelioration of appetite, fatigue, depression and sleep disorders in breast cancer and terminal cancer patients suffering from a wide variety of cancer types that received complimentary 7.5g IVC while being treated by respective standard regimens.

More recently, a single-centre, parallel-group, single-blind interventional study also in breast cancer patients [13] showed a similar and significant reduction of symptoms such as nausea, fatigue, tumour pain and loss of appetite by administering 25g of IVC per week in addition to their current standard treatment.

Favourably, no new side effects were reported after the initiation of IVC treatment.

Moreover, another retrospective study showed that patients with radiotherapy-resistant bone metastasis not only had less pain and better performance measures when given high-dose VitC, but they also had a median survival time of 10 months as compared to the 2 months median survival time within the control group [7].

Conclusion:

Vitamin C has a complex history as a potential cancer treatment, with mixed results from small clinical trials.

However, recent preclinical studies have shed light on the potential benefits of high-dose vitamin C for cancer patients, and have identified biomarkers and patient populations that may respond well to the therapy.

Overall, high-dose Vit C administered as a single agent has not only been shown to be safe and well-tolerated in cancer patients but also to ameliorate pain and to improve quality of life in the palliative care setting.

References

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References for IVC monotherapy in palliative care and quality of life (EOL)

1. Polireddy K, Dong R, Reed G, Yu J, Chen P, Williamson S, et al. High dose parenteral Ascorbate inhibited pancreatic Cancer growth and metastasis: mechanisms and a phase I/IIa study. Sci Rep. 2017;7(1):17188.
2. Takahashi H, Mizuno H, Yanagisawa A. High‐dose intravenous vitamin C improves quality of life in cancer patients. Pers Med Universe. 2012;1(1):49–53.
3. Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo−/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011;25(6):983–90.
4. Yeom CH, Jung GC, Song KJ. Changes of terminal Cancer patients’ health‐related quality of life after high dose vitamin C administration. J Korean Med Sci. 2007;22(1):7.
5. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy. Sci Transl Med. 2014;6(222):222ra18.
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